Prostaglandin synthase-2 inhibitors

ABSTRACT

The present invention provides a compound of the formula: ##STR1## Such compounds are useful for inhibiting prostaglandin synthesis. Pharmaceutical compositions and methods for inhibiting prostaglandin synthesis are also disclosed.

This is a division of U.S. patent application Ser. No. 08/744,906, filedNov. 8, 1996, now U.S. Pat. No. 5,681,842.

TECHNICAL FIELD

This invention relates to novel compounds having activity to inhibitprostaglandin biosynthesis, to pharmaceutical compositions comprisingthese compounds and to a medical method of treatment. More particularly,this invention concerns fused carbocyclic or fused heterocycliccontaining derivatives of sulfonamides which inhibit prostaglandinbiosynthesis, particularly the induced prostaglandin endoperoxide Hsynthase (PGHS-2, but also known as cyclooxygenase-2 (COX-2)), topharmaceutical compositions comprising these compounds and to a methodof inhibiting prostaglandin biosynthesis.

BACKGROUND OF THE INVENTION

The prostaglandins are extremely potent substances which produce a widevariety of biological effects, often in the nanomolar to picomolarconcentration range. The discovery of two forms of prostaglandinendoperoxide H synthase-1 and -2 (PGHS-1 and PGHS-2) that catalyze theoxidation of arachidonic acid leading to prostaglandin biosynthesis hasresulted in renewed research to delineate the role of these two isozymesin physiology and pathophysiology. These isozymes have been shown tohave different gene regulation and represent distinctly differentprostaglandin biosynthesis pathways. The PGHS-1 pathway is expressedconstitutively in most cell types. It responds to produce prostaglandinsthat regulate acute events in vascular homeostasis and also has a rolein maintaining normal stomach and renal function. The newly discoveryPGHS-2 pathway involves an induction mechanism which has been linked toinflammation, mitogenesis and ovulation phenomena.

Prostaglandin inhibitors provide therapy for pain, fever andinflammation for example, in the treatment of rheumatoid arthritis andosteoarthritis. The non-steroidal antiinflammatory drugs (NSAIDs) suchas ibuprofen, naproxen and fenamates inhibit both isozymes, i.e.prostaglandin endoperoxide H synthase 1 (PGHS-1) and prostaglandinendoperoxide H synthase 2 (PGHS-2). Inhibition of the constitutiveenzyme PGHS-1 results in gastrointestinal side effects including ulcersand bleeding and incidence of renal problems with chronic therapy.

Inhibitors of the induced isozyme PGHS-2 are proposed to provideantiinflammatory activity without the side effects of PGHS-1 inhibitors.A general review of the current knowledge of PGHS-1 and PGHS-2 isozymeproperties and a summary of inhibitors and their activity has beenreviewed by: (1) Battistini, B.; Botting, R.; Bakhle, Y. S., "COX-1 andCOX-2: Toward the Development of More Selective NSAIDs", Drug News andPerspectives, 7(8): 501-512 (1994); (2) DeWitt, D. L.; Bhattacharyya,D.; Lecomte, M.; Smith, W. L., "The Differential Susceptibility ofProstaglandin Endoperoxide H Synthases-1 and -2 to NonsteroidalAnti-inflammatory Drugs: Aspirin Derivatives as Selective Inhibitors",Med. Chem. Res. 5(5): 325-343 (1995); and (3) Mitchell, J. A.: Larkin,S.; Williams, T. J. Cyclooxgenase-2: regulation and relevance ininflammation. Biochem. Pharm 1995, 50(10), 1535-1542.

The current invention provides novel fused carbocyclic or fusedheterocyclic containing derivatives of sulfonamides with unexpectedpreferential inhibitory activity against the induced PGHS-2 isozymeversus PGHS-1.

SUMMARY OF THE INVENTION

The present invention provides novel naphthyl and fused heterocyclecontaining derivatives of sulfonamide compounds with unexpectedpreferential inhibitory activity against induced PGHS-2 isozyme versusPGHS-1.

In its principal embodiment, the present invention provides a compoundof the formula: ##STR2## wherein Z is selected from the group consistingof (a) naphthyl; (b) substituted naphthyl wherein the hydrogen atomattached to one to four of the carbon atoms is replaced with asubstituent independently selected from R₄ wherein R₄ is --F, --CN,--Cl, or --CF₃ ; (c) benzthiazol-5-yl; (d) substituted benzthiazol-5-ylwherein the hydrogen atom attached to one to four of the carbon atoms isreplaced with a substituent independently selected from R₄ wherein R₄ isas defined above; (e) benzthiazol-6-yl; (f) substituted benzthiazol-6-ylwherein the hydrogen atom attached to one to four of the carbon atoms isreplaced with a substituent independently selected from R₄ wherein R₄ isas defined above; (g) benzoxazol-5-yl; (h) substituted benzoxazol-5-ylwherein the hydrogen atom attached to one to four of the carbon atoms isreplaced with a substituent independently selected from R₄ wherein R₄ isas defined above; (i) benzoxazol-6-yl; (j) substituted benzoxazol-6-ylwherein the hydrogen atom attached to one to four of the carbon atoms isreplaced with a substituent independently selected from R₄ wherein R₄ isas defined above; (k) benzthiophen-5-yl; (l) substitutedbenzthiophen-5-yl wherein the hydrogen atom attached to one to four ofthe carbon atoms is replaced with a substituent independently selectedfrom R₄ wherein R₄ is as defined above; (m) benzthiophen-6-yl; (n)substituted benzthiophen-6-yl wherein the hydrogen atom attached to oneto four of the carbon atoms is replaced with a substituent independentlyselected from R₄ wherein R₄ is as defined above; (o) benzimidazol-5-ylwherein the hydrogen atom attached to the nitrogen atom is optionallysubstituted with lower alkyl; (p) substituted benzimidazol-5-yl whereinthe hydrogen atom attached to the nitrogen atom is optionallysubstituted with lower alkyl and the hydrogen atom attached to one tofour of the carbon atoms is replaced with a substituent independentlyselected from R₄ wherein R₄ is as defined above; (q) benzimidazol-6-ylwherein the hydrogen atom attached to the nitrogen atom is optionallysubstituted with lower alkyl; (r) substituted benzimidazol-6-yl whereinthe hydrogen atom attached to the nitrogen atom is optionallysubstituted with lower alkyl and the hydrogen atom attached to one tofour of the carbon ring atoms is replaced with a substituentindependently selected from R₄ wherein R₄ is as defined above; (s)1,3-benzodioxol-5-yl; (t) substituted 1,3-benzodioxol-5-yl wherein thehydrogen atom attached to one or two of the carbon ring atoms isreplaced with a substituent independently selected from R₄ wherein R₄ isas defined above; (u) benzofur-5-yl; (v) substituted benzofur-5-ylwherein the hydrogen atom attached to one to four of the carbon ringatoms is replaced with a substituent independently selected from R₄wherein R₄ is as defined above; (w) benzofur-6-yl; (x) substitutedbenzofur-6-yl wherein the hydrogen atom attached to one to four of thecarbon ring atoms is replaced with a substituent independently selectedfrom R₄ wherein R₄ is as defined above; (y) indol-5-yl wherein thehydrogen atom attached to the nitrogen atom is optionally substitutedwith lower alkyl; (z) substituted indol-5-yl wherein the hydrogen atomattached to the nitrogen atom is optionally substituted with lower alkyland wherein the hydrogen atom attached to one to four of the carbon ringatoms is replaced with a substituent independently selected from R₄wherein R₄ is as defined above; (aa) indol-6-yl wherein the hydrogenatom attached to the nitrogen atom is optionally substituted with loweralkyl; and (bb) substituted indol-6-yl wherein the hydrogen atomattached to the nitrogen atom is optionally substituted with lower alkyland wherein the hydrogen atom attached to one to four of the carbon ringatoms is replaced with a substituent independently selected from R₄wherein R₄ is as defined above;

R₁ is selected from the group consisting of --NO₂, --CN, --Cl, and CF₃ ;

R₂ is --H or R₁ and R₂ taken together with the atoms to which they areattached define a 5-, 6- or 7-membered saturated carbocyclic orsaturated heterocyclic ring having a single heteroatom selected fromoxygen, nitrogen or sulfur wherein the carbocyclic or heterocyclic ringis unsubstituted or substituted with one or two substituents selectedfrom the group consisting of oxo, alkyl and hydroxyl; and

R₃ is selected from the group consisting of lower alkyl and CH_(n)F.sub.(3-n) wherein n is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt or prodrug thereof.

In another embodiment, the present invention also providespharmaceutical compositions useful for inhibiting prostaglandinbiosynthesis comprising a therapeutically effective amount of a compoundof the invention in combination with a pharmaceutically acceptablecarrier.

In yet another embodiment, the present invention provides a method ofinhibiting prostaglandin biosynthesis in a host mammal comprisingadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a compound of the invention.

DETAILED DESCRIPTION OF THE INVENTION

As used throughout this specification and the appended claims, thefollowing terms have the meanings specified.

The term "alkanoyl" as used herein refers to R₅ C(O)-- wherein R₅ is alower alkyl group.

The term "alkoxy" as used herein refers to R₆ O-- wherein R₆ is a loweralkyl group.

The term "alkoxycarbonyl" as used herein refers to R₇ C(O)-- wherein R₇is an alkoxy group.

The term "alkyl" as used herein refers to a monovalent group derivedfrom a straight or branched chain saturated C₁ -C₁₂ hydrocarbon by theremoval of a single hydrogen atom.

The term "alkylamino" as used herein refers to --NHR₈ wherein R₈ is alower alkyl group.

The term "aminocarbonyl" as used herein refers to --C(O)NH₂.

The term "aroyl" as used herein refers to R₉ C(O)-- wherein R₉ is anaryl group.

The term "aryl" as used herein refers to a mono- or bicyclic carbocyclicring system comprising 6 to 12 carbon atoms and having one or twoaromatic rings including, but not limited to, phenyl, naphthyl,tetrahydronaphthyl, indanyl, indenyl and the like. Aryl groups can beunsubstituted or substituted with one, two, three or four substituentsindependently selected from lower alkyl, halo, haloalkyl, haloalkoxy,alkoxy, alkoxycarbonyl, thioalkoxy, amino, alkylamino, dialkylamino,aminocarbonyl, mercapto, nitro, carboxaldehyde, carboxy and hydroxy.

The term "dialkylamino" as used herein refers to --NR₁₀ R₁₁ wherein R₁₀and R₁₁ are independently selected from lower alkyl groups.

The term "halo" as "halogen" as used herein refers to --Cl, --F, --Br,or --I.

The term "haloalkyl" as used herein refers to a lower alkyl group inwhich one or more hydrogen atoms are replaced by halogen, for example,chloromethyl, chloroethyl, trifluoromethyl and the like.

The term "haloalkoxy" as used herein refers to R₁₂ O-- wherein R₁₂ is ahaloalkyl group.

The term "heterocyclic" or "heterocycle" or "heterocyclic ring" as usedherein refers to a 5-, 6- or 7-membered ring containing one, two orthree heteroatoms independently selected from the group consisting ofnitrogen, oxygen and sulfur or a 5-membered ring containing 4 nitrogenatoms; and includes a 5-, 6- or 7-membered ring containing one, two orthree nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen andone sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms innon-adjacent positions; one oxygen and one sulfur atom in non-adjacentpositions; two sulfur atoms in non-adjacent positions; two sulfur atomsin adjacent positions and one nitrogen atom; and two adjacent nitrogenatoms and one sulfur atom; two non-adjacent nitrogen atoms and onesulfur atom; two non-adjacent nitrogen atoms and one oxygen atom. The5-membered ring has 0-2 double bonds and the 6- and 7-membered ringshave 0-3 double bonds. The nitrogen heteroatoms can be optionallyquaternized.

Heterocyclics can be unsubstituted or substituted with one, two, threeor four substituents independently selected from the group consisting ofhydroxy, halo, oxo (═O), alkoxy, haloalkyl, and lower alkyl. Inaddition, nitrogen containing heterocycles can be N-protected.

The term lower alkyl as used herein refers to a monovalent group derivedfrom a straight or branched chain saturated C₁ -C₈ hydrocarbon by theremoval of a single hydrogen atom. Loweralkyl groups are exemplified bymethyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl, and thelike.

The term "thioalkoxy" as used herein refers to R₁₀ S-- wherein R₁₀ is alower alkyl group.

Asymmetric centers may exist in the compounds of the present invention.The present invention contemplates the various stereoisomers andmixtures thereof. Individual stereoisomers of compounds of the presentinvention are made by synthesis from starting materials containing thechiral centers or by preparation of mixtures of enantiomeric productsfollowed by separation as, for example, by conversion to a mixture ofdiastereomers followed by separation by recrystallization orchromatographic techniques, or by direct separation of the opticalenantiomers on chiral chromatographic columns. Starting compounds ofparticular stereochemistry are either commercially available or are madeby the methods detailed below and resolved by techniques well known inthe organic chemical arts.

In its principal embodiment, the present invention provides a compoundhaving the formula: ##STR3## wherein Z is selected from the groupconsisting of:

(a) naphthyl;

(b) substituted naphthyl wherein the hydrogen atom attached to one tofour of the carbon atoms is replaced with a substituent independentlyselected from R₄ wherein R₄ is --F, --CN, --Cl, or --CF₃ ;

(c) benzthiazol-5-yl;

(d) substituted benzthiazol-5-yl wherein the hydrogen atom attached toone to four of the carbon atoms is replaced with a substituentindependently selected from R₄ wherein R₄ is as defined above;

(e) benzthiazol-6-yl;

(f) substituted benzthiazol-6-yl wherein the hydrogen atom attached toone to four of the carbon atoms is replaced with a substituentindependently selected from R₄ wherein R₄ is as defined above;

(g) benzoxazol-5-yl;

(h) substituted benzoxazol-5-yl wherein the hydrogen atom attached toone to four of the carbon atoms is replaced with a substituentindependently selected from R₄ wherein R₄ is as defined above;

(i) benzoxazol-6-yl;

(j) substituted benzoxazol-6-yl wherein the hydrogen atom attached toone to four of the carbon atoms is replaced with a substituentindependently selected from R₄ wherein R₄ is as defined above;

(k) benzthiophen-5-yl;

(l) substituted benzthiophen-5-yl wherein the hydrogen atom attached toone to four of the carbon atoms is replaced with a substituentindependently selected from R₄ wherein R₄ is as defined above;

(m) benzthiophen-6-yl;

(n) substituted benzthiophen-6-yl wherein the hydrogen atom attached toone to four of the carbon atoms is replaced with a substituentindependently selected from R₄ wherein R₄ is as defined above;

(o) benzimidazol-5-yl wherein the hydrogen atom attached to the nitrogenatom is optionally substituted with lower alkyl;

(p) substituted benzimidazol-5-yl wherein the hydrogen atom attached tothe nitrogen atom is optionally substituted with lower alkyl and thehydrogen atom attached to one to four of the carbon atoms is replacedwith a substituent independently selected from R₄ wherein R₄ is asdefined above;

(q) benzimidazol-6-yl wherein the hydrogen atom attached to the nitrogenatom is optionally substituted with lower alkyl;

(r) substituted benzimidazol-6-yl wherein the hydrogen atom attached tothe nitrogen atom is optionally substituted with lower alkyl and thehydrogen atom attached to one to four of the carbon ring atoms isreplaced with a substituent independently selected from R₄ wherein R₄ isas defined above;

(s) 1,3-benzodioxol-5-yl;

(t) substituted 1,3-benzodioxol-5-yl wherein the hydrogen atom attachedto one or two of the carbon ring atoms is replaced with a substituentindependently selected from R₄ wherein R₄ is as defined above;

(u) benzofur-5-yl;

(v) substituted benzofur-5-yl wherein the hydrogen atom attached to oneto four of the carbon ring atoms is replaced with a substituentindependently selected from R₄ wherein R₄ is as defined above;

(w) benzofur-6-yl;

(x) substituted benzofur-6-yl wherein the hydrogen atom attached to oneto four of the carbon ring atoms is replaced with a substituentindependently selected from R₄ wherein R₄ is as defined above;

(y) indol-5-yl wherein the hydrogen atom attached to the nitrogen atomis optionally substituted with lower alkyl;

(z) substituted indol-5-yl wherein the hydrogen atom attached to thenitrogen atom is optionally substituted with lower alkyl and wherein thehydrogen atom attached to one to four of the carbon ring atoms isreplaced with a substituent independently selected from R₄ wherein R₄ isas defined above;

(aa) indol-6-yl wherein the hydrogen atom attached to the nitrogen atomis optionally substituted with lower alkyl; and

(bb) substituted indol-6-yl wherein the hydrogen atom attached to thenitrogen atom is optionally substituted with lower alkyl and wherein thehydrogen atom attached to one to four of the carbon ring atoms isreplaced with a substituent independently selected from R₄ wherein R₄ isas defined above;

R₁ is selected from the group consisting of --NO₂, --CN, --Cl, and CF₃ ;

R₂ is --H or R ₁ and R₂ taken together with the atoms to which they areattached define a 5-, 6- or 7-membered saturated carbocyclic orsaturated heterocyclic ring having a single heteroatom selected fromoxygen, nitrogen or sulfur wherein the carbocyclic or heterocyclic ringis unsubstituted or substituted with one or two substituents selectedfrom the group consisting of oxo, alkyl and hydroxyl; and

R₃ is selected from the group consisting of lower alkyl and CH_(n)F.sub.(3-n) wherein n is 0, 1, 2 or 3;

or a pharmaceutically acceptable salt or prodrug thereof.

Preferred compounds of the invention are compounds of formula I whereinZ and R₃ are as defined above and R₁ and R₂ taken together with theatoms to which they are attached define a 5-membered saturatedcarbocyclic ring substituted with oxo.

More preferred compounds of the invention are compounds of formula Iwherein Z is as defined above, R₁ is --NO₂, R₂ is --H and R₃ is CH₃.

Even more preferred compounds of the invention are compounds of formulaI wherein Z is (a) naphthyl; (b) substituted naphthyl wherein thehydrogen atom attached to one to four of the carbon atoms is replacedwith a substituent independently selected from R₄ wherein R₄ is asdefined above; (c) benzthiazol-6-yl; (d) substituted benzthiazol-6-ylwherein the hydrogen atom attached to one to four of the carbon atoms isreplaced with a substituent independently selected from R₄ wherein R₄ isas defined above; (e) benzthiophen-5-yl; (f) substitutedbenzthiophen-5-yl wherein the hydrogen atom attached to one to four ofthe carbon atoms is replaced with a substituent independently selectedfrom R₄ wherein R₄ is as defined above; (g) 1,3-benzodioxol-6-yl; (h)substituted 1,3-benzodioxol-6-yl wherein the hydrogen atom attached toone to four of the carbon atoms is replaced with a substituentindependently selected from R₄ wherein R₄ is as defined above; R₁ is--NO₂, R₂ is --H; and R₃ is --CH₃.

Even more preferred compounds of formula I are:

N-(4-Nitro-2-(naphth-2'-yloxy)phenyl)methanesulfonamide;

N-(4-Nitro-2-(6'-fluoronaphth-2'-yloxy)phenyl)methanesulfonamide;

N-(4-Nitro-2-(benzothiophen-5'-yloxy)phenyl)methanesulfonamide;

N-(4-Nitro-2-(benzothiazol-6'-yloxy)phenyl)methanesulfonamide; and

N-(4-Nitro-2-(1,3-benzodioxol-5'-yloxy)phenyl)methanesulfonamide or apharmaceutically acceptable salt or prodrug thereof.

By pharmaceutically acceptable salt it is meant those salts which are,within the scope of sound medical judgement, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity,irritation, allergic response and the like, and are commensurate with areasonable benefit/risk ratio. Pharmaceutically acceptable salts arewell known in the art. For example, S. M. Berge, et al. describepharmaceutically acceptable salts in detail in J. PharmaceuticalSciences, 66: 1-19 (1977). The salts can be prepared in situ during thefinal isolation and purification of the compounds of the invention, orseparately by reacting the free base function with a suitable organicacid. Representative acid addition salts include acetate, adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphersulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate,hexanoate, hydrobromide, hydrochloride, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, toluenesulfonate, undecanoate, valerate salts, and thelike. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, magnesium, and the like, as well asnontoxic ammonium, quaternary ammonium, and amine cations, including,but not limited to ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine,and the like.

As used throughout this specification and the appended claims, the term"metabolically cleavable group" denotes a moiety which is readilycleaved in vivo from the compound bearing it, which compound aftercleavage remains or becomes pharmacologically active. Metabolicallycleavable groups form a class of groups reactive with the aminosulfonylgroup of the compounds of this invention. Such metabolically cleavablegroups are well known to those of ordinary skill in the art and include,but are not limited to such groups as alkanoyl (such as acetyl,propionyl, butyryl, and the like), unsubstituted and substituted aroyl(such as benzoyl and substituted benzoyl), alkoxycarbonyl (such asethoxycarbonyl), trialkylsilyl (such as trimethyl- and triethylsilyl),monoesters formed with dicarboxylic acids (such as succinyl) and thelike.

Because of the ease with which the metabolically cleavable groups of thecompounds of this invention are cleaved in vivo, the compounds bearingsuch groups act as prodrugs of other prostaglandin biosynthesisinhibitors. The compounds bearing the metabolically cleavable groupshave the advantage that they may exhibit improved bioavailability as aresult of enhanced solubility and/or rate of absorption conferred uponthe parent compound by virture of the presence of the metabolicallycleavable group. A thorough discussion of prodrugs is provided in T.Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Vol 14 ofthe A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein byreference.

The compounds of the invention are selective inhibitors of PGHS-2. AsPGHS-2 inhibitors, these compounds are useful in the treatment ofconditions which are mediated by PGHS-2 activity. More particularly,these compounds are useful for treating or modulating pathologicalconditions in mammals which are associated with the production ofprostaglandins by PGHS-2. Thus, the compound is useful as ananti-inflammatory agent for treating both acute inflammatory conditions(such as those resulting from infection) and chronic inflammatoryconditions (such as those resulting from asthma, arthritis andinflammatory bowel disease). It is also useful as an analgesic andanti-pyretic agent (i.e. for reducing pain and fever). Further uses arefor the prevention of cardiovascular disease, the prevention of boneresorption and for the reduction of colon cancer.

Prostaglandin Inhibition Analysis

I. Methodologies

a. Recombinant Human PGHS-1 and PGHS-2 Enzyme Assays: A compound of theinvention dissolved in DMSO (3.3% v/v) was preincubated with microsomesfrom recombinant human PGHS-1 or PGHS-2 expressed in the baculovirus/Sf9cell system (Gierse, J. K., Hauser, S. D., Creely, D. P., Koboldt, C.,Rangwala, S., H., Isakson, P. C., and Seibert, K. "Expression andselective inhibition of the constitutive and inducible forms ofcyclooxygenase", Biochem J. 305: 479 (1995)), together with thecofactors phenol (2 mM) and hematin (1 μM) for 60 minutes prior to theaddition of 10 μM arachidonic acid. The reaction was allowed to run for2.5 minutes at room temperature prior to quenching with HCl andneutralization with NaOH. PGE₂ production in the presence and absence ofthe drug was determined by EIA analysis.

b. EIA Determination of Prostaglandins: EIA reagents for prostaglandindetermination were purchased from Perseptive Diagnostics, Cambridge,Mass. PGE₂ levels in lavage fluids were determined after the sampleswere dried under nitrogen and reconstituted with assay buffer. PGE₂levels in enzyme assays or cell culture media were measured againststandards prepared in the same milieu. The immunoassays were conductedas recommended by the manufacturer. The EIA was conducted in 96 wellmicrotiter plates (Nunc Roskilde, Denmark) and optical density measuredusing a microplate reader (Vmax, Molecular Devices Corp., Menlo Park,Calif.).

c. Carrageenan Induced Pleurisy Test (CIP): Inhibition of carrageenaninduced pleurisy in rats was determined essentially as described by F.B. De Brito, (Pleurisy and Pouch Models of Acute Inflammation inPharmalogical Methods in the Control of Inflammation, Eds, J. Y. Changand A. J. Lewis, Alan Liss Inc., New York: 173-194, 1989) and Vinegar etal. ("Quantitative studies of the pathway to acute carrageenaninflammation", Fed. Proc., 35: 2447-2456 (1976)). Briefly, eightSprague-Dawley rats were orally dosed with 10 mg/kg of a compound of theinvention 30 minutes prior to intrapleural injection of 2% lambdacarrageenan (Sigma Chemical Co., St. Louis Mo.). Four hours aftercarrageenan injection, the animals were euthanized and their pleuralcavities lavaged with ice cold saline. The lavage fluid was then addedto two volumes of ice cold methanol (final methanol concentration 66%)to lyse cells and precipitate protein. Prostaglandin levels in themethanol/lavage fluid were then determined by EIA.

II. In vitro Assay Results

When tested in the recombinant human PGHS-1 and PGHS-2 enzyme assays asdescribed above, all representative compounds were shown to be potentinhibitors of recombinant human PGHS-2, with compound 5 being mostpotent. (Please see Table 1). Furthermore, all representative compoundswere shown to be more selective inhibitors of recombinant human PGHS-2than recombinant human PGHS-1.

                  Table 1                                                         ______________________________________                                        In Vitro Inhibitory Potencies Against Human Recombinant                       PGHS-1 and PGHS-2                                                             Example                                                                              RHnPGHS-2 (% I @ 100 nM)                                                                       RHuPGHS-1 (% I @ 100 μM)                           ______________________________________                                        1      65%              47%                                                   2      56%              26%                                                   3      59%              89%                                                   4      43%              31%                                                   5      77%              89%                                                   ______________________________________                                    

III. In vivo Results

When tested in the carrageenan induced pleurisy assay, the compounds ofExamples 2, 3, 4, and 5 were shown to inhibit prostaglandin productionin the pleural cavity by 20, 48, 66 and 36% respectively.

Pharmaceutical Compositions

The present invention also provides pharmaceutical compositions whichcomprise compounds of the present invention formulated together with oneor more non-toxic pharmaceutically acceptable carriers. Thepharmaceutical compositions may be specially formulated for oraladministration in solid or liquid form, for parenteral injection, or forrectal administration.

The pharmaceutical compositions of this invention can be administered tohumans and other animals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, or as an oral or nasal spray.The term "parenteral" administration as used herein refers to modes ofadministration which include intravenous, intramuscular,intraperitoneal, intrasternal, subcutaneous and intraarticular injectionand infusion.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol, and the like), and suitable mixtures thereof, vegetable oils(such as olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservative,wetting agents, emulsifying agents, and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents such as sugars, sodium chloride,and the like. Prolonged absorption of the injectable pharmaceutical formmay be brought about by the inclusion of agents which delay absorptionsuch as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides) Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, and tragacanth, and mixturesthereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals that are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andthe phosphatidyl cholines (lecithins), both natural and synthetic.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers, or propellants which maybe required. Opthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions, and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated, and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required for toachieve the desired therapeutic effect and to gradually increase thedosage until the desired effect is achieved.

Generally dosage levels of about 1 to about 50, more preferably of about5 to about 20 mg of active compound per kilogram of body weight per dayare administered orally to a mammalian patient. If desired, theeffective daily dose may be divided into multiple doses for purposes ofadministration, e.g. two to four separate doses per day.

Preparation of Compounds of this Invention

The methanesulfonamide compounds of the invention can be prepared asshown in Schemes 1 and 2. As outlined in Scheme 1, compound I, (which iscommercially available) is first protected with a t-butyldimethylsilylgroup under standard reaction conditions. The resulting silyl ether (II)is converted to the bis(sulfonamide) by treatment with two equivalentsof a base, such as sodium hydride, and two equivalents of alkylsulfonylchloride or fluorinated alkylsulfonyl chloride in a solvent such asdimethylformamide. Deprotection of the t-butyldimethylsilyl group occursconcomitantly during the quenching of the sulfonylation reaction toprovide the bis(sulfonylamino)phenol (III). Mono-deprotection isachieved by exposing compound III to a refluxing solution of aqueousethanol and an alkali metal hydroxide such as lithium hydroxide. Theresulting sulfonylaminophenol (IV), is converted to a compound of theinvention by heating in a solvent, such as dimethylformamide, in thepresence of an alkali metal salt, such as potassium carbonate, and acopper halogen salt, such as copper iodide, and a compound Z of theinvention which is halogenated with bromine or iodine. ##STR4##

Alternatively, in Scheme 2, commercially available starting compound Vis converted to the corresponding methanesulfonamide by treatment with abase, such as sodium hydride, and alkylsulfonyl chloride or fluorinatedalkylsulfonyl chloride in a solvent such as dimethylformamide. Theresulting (sulfonylamino)arylbromide (VI), is converted to a compound ofthe invention by heating in a solvent, in the presence of an alkalimetal salt, and a copper halogen salt, (as described in Scheme 1), and acompound Z of the invention substituted with --OH. ##STR5##

Trifluoromethanesulfonamide compounds may be prepared according toScheme 3 below. As shown in Scheme 3, a methanesulfonamide compound ofthe invention is hydrolyzed by refluxing in a strong protic acid such assulfuric acid in the presence of water and acetic acid. The resultinganiline intermediate (VIII) is then converted to abis(trifluorosulfonamide) intermediate (VIII) by treatment withtrifluoromethanesulfonic anhydride at a temperature from about -23° C.about 0° C. in the presence of a hindered amine such as lutidine and asolvent such as dichloromethane. Intermediate VIII is thenmonodeprotected by exposure to an aqueous solution of an alkali metalhydroxide, such as sodium hydroxide, in a solvent such as THF to yield atrifluoromethanesulfonamide compound of the invention. ##STR6##

Table 2 depicts structurally certain preferred compounds of theinvention. In Table 2, a line crossing through both rings to R₄indicates that the R₄ substituent may be present on one or both rings.Furthermore, R₄ may be substituted at 0-4 positions which areindependently selected from the group consisting of --F, --CN, --Cl, andCF₃. R₅ is --H or lower alkyl and R₆ at each occurrence is independentlyselected from the group consisting of --H and --CH₃. Y represents NR₅, Oor S.

                  TABLE 2                                                         ______________________________________                                         ##STR7##                                                                     Z              R.sub.1    R.sub.2                                                                             R.sub.3                                       ______________________________________                                         ##STR8##                                                                                     ##STR9##  H     C.sub.1 -C.sub.8 alkyl CH.sub.n F.sub.(3-n                                    ) wherein n = 0-3                              ##STR10##                                                                     ##STR11##                                                                     ##STR12##                                                                     ##STR13##                                                                     ##STR14##                                                                     ##STR15##                                                                    ______________________________________                                    

The foregoing may be better understood by reference to the followingexamples which are provided for illustration and not intended to limitthe scope of the inventive concept. Both below and throughout thespecification it is intended that citations to the literature areexpressly incorporated by reference.

EXAMPLE 1 N-(4-Nitro-2-(naphth-2'-yloxy)phenyl)methanesulfonamide##STR16##

A mixture of 2-bromonaphthalene (0.16 g, 0.77 mmol),N-(2-hydroxy-4-nitrophenyl)methanesulfonamide (0.15 g, 0.65 mmol),potassium carbonate (0.22 g, 1.61 mmol), and copper(I) iodide (0.12 g,0.65 mmol) in dry DMF (6.5 mL) was stirred at reflux under N₂ for 3hours. The resulting black reaction mixture was partitioned betweenethyl acetate and saturated aqueous ammonium chloride. The aqueous layerwas separated, and the organic layer was washed (saturated aqueousammonium chloride, 1×; water,1×; brine, 1×), dried (MgSO₄), filtered,and evaporated in vacuo. Purification by flash column chromatography(silica gel; 1:1 dichloromethane/hexanes) provided 0.073 g (30%) of thedesired product. Recrystallization from ethyl acetate/hexanes gaveN-(4-Nitro-2-(naphth-2'-yloxy)phenyl)methanesulfonamide as a colorlesssolid: mp 167°-168° C.; ¹ H NMR (300 MHz, CDCL₃) δ3.20 (s, 3H), 7.24(dd, J=9 Hz, J=2.5 Hz, 1H), 7.44 (s, 1H), 7.47 (d, J=2.5 Hz, 1H), 7.55(m, 2H), 7.69 (d, J=2.5 Hz, 1H), 7.80 (dd, J=8 Hz, 2.5 Hz, 1H), 7.81 (d,J=9 Hz, 1H), 7.91 (m, 1H), 7.95 (d, J=9Hz, 1H), 8.04 (dd, J=9Hz, J=2.5Hz, 1H); MS (DCI-NH₃) m/z 376 (M+NH₄)⁺. Anal. Calcd for C₁₇ H₁₄ N₂ O₅ S:C, 56.27; H, 4.03; N, 7.72. Found: C, 56.21 H, 3.95; N, 7.59.

Preparation of N-(2-hydroxy-4-nitrophenyl)methanesulfonamide

To a magnetically stirred solution of 2-amino-5-nitrophenol (5.62 g,36.5 mmol) and chloro-t-butyldimethylsilane (5.00 g, 33.2 mmol) in drydichloromethane (66 mL) was added triethylamine (5.55 mL, 39.8 mmol) at25° C. The reaction mixture was stirred at ambient temperature for 4hours and partitioned between diethyl ether (200 mL) and saturatedammonium chloride. The aqueous layer was separated and the ether layerwashed (saturated ammonium chloride, 1×; water, 1×; brine, 1×), dried(MgSO₄), filtered, and evaporated in vacuo. Crystallization from ethylacetate/hexanes gave 7.5 g (84%) ofO-t-butyldimethylsilyl-2-amino-5-nitrophenol.

O-t-butyldimethylsilyl-2-amino-5-nitrophenol (1.50 g, 5.6 mmol) in drydimethylformamide (DMF, 5 mL) was added to a suspension of sodiumhydride (704 mg; 60% in mineral oil) in dry DMF (11 mL) at 0° C. Afterthe evolution of hydrogen had ended, the orange mixture was stirred at25° C. for 30 minutes. Methanesulfonyl chloride (0.91 mL, 11.7 mmol) wasadded drop wise via a syringe, and the reaction mixture was stirred at25° C. for 17 hours. The mixture was poured into saturated ammoniumchloride (50 mL) and extracted with ethyl acetate (3×100 mL). Thecombined organic layers were washed (saturated ammonium chloride, 1×;water, 1×; brine, 1×), dried (MgSO₄), filtered, and evaporated in vacuo.Crystallization from methanol/ethyl acetate/hexanes provided 0.96 g(55%)of N,N-bis(methanesulfonamido)-2-hydroxy4-nitro-aniline as a colorlesssolid.

A mixture of N,N-bis(methanesulfonamido)-2-hydroxy4-nitroaniline (0.90g, 2.9 mmol) and lithium hydroxide (0.51 g, 12.2 mmol) in 2:1 ethanol:H₂O (15 mL) was stirred at reflux for 17 hours. The reaction mixture waspoured into aqueous saturated ammonium chloride and extracted with ethylacetate (3×100 mL). The combined organic layers were dried(MgSO₄),filtered, and evaporated in vacuo. Crystallization from ethylacetate-hexanes gave N-(2-hydroxy4-nitrophenyl)methanesulfonamide as ayellow solid: mp 180°-181.5° C.

EXAMPLE 2N-(4-Nitro-2-(6'-fluoro-naphth-2'-yloxy)phenyl)methanesulfonamide##STR17##

To a solution of 6-fluoro-naphth-2-ol (510 mg, 3.14 mmol) prepared inDMF (20 mL) at room temperature was addedN-(4-Nitro-2-bromophenyl)methanesulfonamide (925 mg, 3.51 mmol). Thereaction was heated at reflux for 7 hours and cooled to roomtemperature. The reaction was quenched with 10% aqueous HCl. Celite wasadded to the two phased solution and the resulting mixture was filtered.The filter cake was washed thoroughly with ethyl acetate. The organiclayer was drawn off and the aqueous layer was extracted with ethylacetate (100 mL, 2×). The combined extracts were diluted with an equalvolume of hexanes and the resulting solution washed (H₂ O, 2×; brine,2×), dried (Na₂ SO₄), filtered and concentrated in vacuo to afford adark brown thick oil that was purified by flash chromatography (silicagel; 20% EtOAc/Hexane) to afford the desired product as a white solidwhich was recrystallized from acetone/methanol. mp 179°-180° C.; ¹ H NMR(300 MHz, DMSO-d₆) δ3.20 (s, 3H), 7.44-7.52 (m, 2H), 7.65 (m; 2H),7.77-7.82 (m; 2H), 7.95-8.10 (m; 3H), 10.25 (br.s., 1H). MS (DCI-NH₃)m/z 394 (M+NH₄)⁺. Analysis Calc'd for C₁₇ H₁₃ FN₂ O₅ S: C, 54.25; H,3.48; N, 7.44. Found: C, 54.54; H, 3.28; N, 7.29.

Preparation of 6-fluoro-napth-2-ol

A flask was charged with 2-fluoro-6-methoxynapthalene (3.80 g, 21.6mmol) and dichloromethane (86 mL) and cooled to 0° C. in an icebathunder a flow of nitrogen. A solution of borontribromide (26 mL of a 1Msolution in dichloromethane, 25.9 mmol) was added via cannula. Thereaction solution was stirred 15 minutes at 0° C., the cooling bath wasremoved and the reaction was stirred for 1.5 h at ambient temperature.The reaction was quenched by slowly adding excess 10% aqueoushydrochloric acid. The two-phased reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was washed (2×,brine), dried (Na₂ SO₄), filtered and concentrated in vacuo to afford abrown gummy solid. Purification by flash chromatography (silica gel; 20%ethyl acetate/hexane) afforded the desired product (3.63 g, 91% yield).Recrystallization from cold ether/hexanes provided the title compound asa colorless powdery solid. mp 118°-120° C.; ¹ HNMR (300 MHz, DMSO-d₆)δ7.11-7.18 (m; 2H), 7.30 (td; J=9,9,3 Hz; 1H), 7.55 (dd; J=10.5,3 Hz;1H), 7.73-7.79 (m; 2H), 9.73 (s; 1H).

Preparation of 2-fluoro-6-methoxynapthalene

2-amino-6-methoxynapthalene (6.84 g, 39.5 mmol) was converted to thecorresponding tetrafluoroborate diazonium salt following the procedureof Doyle and Bryker (J. Org. Chem. 1979, 44, 1572-1574) usingdichloromethane as the solvent. The resulting diazonium salt wassuspended in chlorobenzene (300 mL) and heated to reflux. Nitrogenevolution began prior to reaching reflux and continued after reflux wasachieved. When gas evolution ceased the reaction was cooled and dilutedwith ethyl acetate. The resulting solution was washed (2×, saturatedsodium bicarbonate; 2×, brine), dried (Na₂ SO₄), filtered andconcentrated in vacuo to afford a brown oil. Purification by flashchromatography (silica gel; 0.25% Acetone/Hexane) afforded the desiredproduct (4.02 g, 58% yield). ¹ HNMR (300 MHz, DMSO-d₆) δ3.86 (s, 3H),7.22 (dd; J=9, 3 Hz; 1H), 7.35 (dd; J=9,3 Hz; 1H), 7.39 (dd; J=7.5,3 Hz;1H), 7.63 (dd; J=10.5,3 Hz; 1H), 7.82 (d; J=10 Hz; 1H), 7.89 (dd; J=10,6Hz; 1H).

Preparation of 2-amino-6-methoxynapthalene

A 2-necked 100 mL round bottom flask was charged with commerciallyavailable 2-acetyl-6-methoxynapthalene(5.0 g, 25 mmol) andtrifluoroacetic acid (500 mmol, 38 mL) and fitted with a refluxcondenser and a stopper. The solution was heated to 120° C. and sodiumazide (3.25 g, 50 mmol) was added over 30 minutes. Each additionresulted in a visible exotherm. Gas evolution ceased 30 minutes aftercomplete addition of the azide. The reaction was cooled and poured intoexcess saturated aqueous sodium bicarbonate. The resulting mixture wasextracted (2×, ethyl acetate). The combined organic extracts were washed(2×, brine), dried (Na₂ SO₄), filtered and concentrated in vacuo toafford a light red solid which was a mixture (˜5:1) of the respectiveN-acetyl-6-methoxynapthylamine andN-methylaminocarbonyl-6-methoxynapthalene. The mixture was carried onwithout purification. The unpurified solid (4.51 g, 20.9 mmol) wasdissolved in hot ethanol (100 mL). Water (15 mL) and concentratedsulfuric acid (2.24 g, 41.9 mmol) were added and the reaction heated atreflux for 24 h during which time a thick precipitate formed. Thereaction was cooled to 0° C. and the solid 2-amino-6-methoxynapthalenehydrogen sulfate salt was collected by filtration. The salt wasneutralized by partitioning between aqueous sodium hydroxide(15.8 g,0.396 mmol in 200 mL of water) and ethyl acetate. The layers wereseparated and the aqueous layer extracted with ethyl acetate (2×). Theorganic layers were combined, washed (brine, 3×), dried (Na₂ SO₄),filtered and concentrated in vacuo to afford a purple solid.Recrystallization from ethyl acetate and acetone gave the title compoundin three fractions (2.64 g, 61%) as a light beige solid. mp 133°-136° C.

Preparation of N-(4-Nitro-2-bromophenyl)methanesulfonamide

Commercially available 2-bromo4-nitroaniline (10.0 g, 46.07 mmol) wasdissolved in DMF (250 mL) and NaH (60% in oil dispersion; 3.7 g, 92.15mmol) added portion wise at 0° C. After 15 minutes, methanesulfonylchloride (10.7 mL, 138.23 mmol) was added and the reaction was stirredovernight at ambient temperature. The reaction was quenched with 1Mcitric acid (100 mL) and extracted with ethyl acetate (3×). The combinedextracts were washed with brine (2×), dried (MgSO₄), filtered andconcentrated in vacuo to yield a red oil that was purified by flashchromatography (silica gel; 20% EtOAc/Hexane) to afford the titlecompound as a yellow solid which was recrystallyzed from ether/hexanes.mp 148°-151° C; ¹ H NMR (300 MHz, DMSO-d₆) δ3.24 (s, 3H), 7.70 (d; J=9Hz; 1H), 8.23 (dd; J=9, 3 Hz; 1H), 8.49 (d; J=3 Hz; 1H), 9.85 (br. s.,1H). MS (DCI-NH₃) m/z 312 (M+NH₄)⁺.

EXAMPLE 3 N-(4-Nitro-2-(benzothiophen-5'-yloxy)phenyl)methanesulfonamide##STR18##

To a solution of 5-hydroxythiophene (1.9 g, 12.66 mmol; prepared by themethod of Zambias, R. and Hammond, M., Syn. Commun., 21(7): 959-964,(1991)) and K₂ CO₃ (9.3 g, 67.52 mmol) in DMF (50 mL) at roomtemperature was added CuCl (1.67 g, 16.88 mmol). The reaction wasstirred for 20 minutes after which N-(4-nitro-2-bromophenyl)methanesulfonamide (2.49 g, 8.44 mmol) prepared as in Example 2 wasadded. The reaction was heated at reflux for 7 hours and allowed to coolto room temperature. The reaction was acidified with 1N HCl (aq) andextracted into EtOAc (3×). The combined extracts were washed with brine(2×), dried (MgSO₄), filtered and concentrated in vacuo to afford abrown oil that was purified by flash chromatography (silica gel; 20%EtOAc/Hexane) and recrystallized from ethyl acetate/hexanes to affordthe desired product. mp 171°-173° C.; ¹ H NMR (300 MHz, DMSO-d₆) δ3.11(s, 3H), 7.22 (dd; J=9, 3 Hz; 1H), 7.44 (d; J=6 Hz; 1H), 7.54 (d; J=3Hz; 1H), 7.68 (d; J=3 Hz; 1H), 7.75 (d; J=9 Hz; 1H), 7.89 (d; J=6 Hz;1), 8.05 (dd; J=9, 3 Hz; 1H), 8.12 (d; J=9 Hz; 1H), 10.21 (bs; 1H). MS(DCI-NH₃) n/z 382 (M+NH₄)⁺ and 364 (M+NH₄ -H₂ O)⁺. Analysis calc'd forC₁₅ H₁₂ N₂ O₅ S₂ : C, 49.44; H, 3.32; N, 7.69. Found: C, 49.08; H, 3.27;N, 7.52.

EXAMPLE 4 N-(-Nitro-2-(benzothiazol-6'-yloxy)phenyl)methanesulfonamide##STR19##

Following the procedure in Example 3, 6-hydroxybenzothiazole (1.0 g,6.61 mmol) was converted to the tide compound and purified by flashchromatography (silica gel; 20% EtOAc/Hexane) and recrystallized fromethyl acetate/hexanes. mp 182°-184° C; ¹ H NMR (300 MHz, DMSO-d₆) δ3.2(s, 3H), 7.39 (dd; J=9, 3 Hz; 1H), 7.63 (d; J=3 Hz; 1H), 7.76 (d; J=9Hz; 1H), 7.96 (d; J=3 Hz; 1H), 8.06 (dd; J=9,3 Hz; 1H),8.18 (d; J=9 Hz;1H), 9.39 (s, 1H), 10.21 (bs; 1H). MS (DCI-NH₃) m/z 383 (M+NH₄)⁺ and 366(M+H)⁺. Analysis calc'd for C₁₄ H₁₁ N₃ O₅ S₂ : C, 46.02; H, 3.03; N,11.5. Found: C, 46.03; H, 2.97; N, 11.28.

EXAMPLE 5N-(4-Nitro-2-(1,3-benzodioxol-6-yloxy)phenyl)methanesulfonamide##STR20##

The title compound was prepared following the procedure in Example 1,but employing 4-bromo-1,2-methylenedioxybenzene (0.74 g, 3.19 mmol) inlieu of 2-bromonaphthalene. Purification by flash chromatography (silicagel; 30% EtOAc/Hexane) and recrystallization from ethyl acetate/hexanesprovided N-(4-Nitro-2-(1,2-methylenedioxy phen-4-yl)phenyl)methanesulfonamide. mp 146°-146.5° C.; ¹ H NMR (300 MHz, DMSO-d₆)δ3.2 (s, 3H), 6.14 (s, 2H), 6.63 (dd; J=9, 3 Hz; 1H), 6.82 (d; J=3 Hz;1H), 7.00 (d; J=9 Hz; 1H), 7.47 (d; J=3 Hz; 1H), 7.69 (d; J=9 Hz; 1H),7.98 (dd; J=9,3 Hz; 1H), 10.07 (s, 1H). MS (DCI-NH₃) m/z 370 (M+NH₄)⁺.Analysis calc'd for C₁₄ H₁₂ N₂ O₇ S: C, 47.73; H, 3.43; N, 7.95. Found:C, 47.80; H, 3.35; N, 7.91.

EXAMPLE 6 N-(2-(naphth-2-yloxy)-4-nitrophenyl)trifluoromethanesulfnamide##STR21##

To a solution ofN-(2-(naphth-2-yloxy)-4-nitrophenyl)-N,N-bis(trifluoromethanesulfonyl)amine(o.428 g, 0.79 mmol) in THF (10 mL) was added excess aqueous sodiumhydroxide (2 mL, 10% aqueous NaOH). The resulting solution was stirredfor 10 minutes at ambient temperature and quenched by adding excess 10%aqueous HCl. The two phased solution was partitioned between ethylacetate and water. The organic layer was washed (2×, brine) dried Na₂SO₄), filtered and concentrated in vacuo. Recrystallization fromether/hexanes afforded the title compound. mp 117°-120° C.; ¹ HNMR (300MHz, CDCL₃) δ7.21(dd; J=9.3 Hz; 1H), 7.53 (d; J=2.5 Hz; 1H), 7.56-7.59(m; 2H), 7.64 (d; J=2.5 Hz; 1H), 7.83 (d; J=9 Hz; 1H), 7.86-8.03 (m=3H);Anal. Calcd for C₁₇ H₁₁ N₂ O₅ F₃ S: C, 49.52; H, 2.69; N, 6.79. Found:C, 49.52; H, 2.69; N, 6.75.

Preparation of N-(2-(naphth-2-yloxy)4-nitrophenyl)-N,Nbis(trifluoromethanesulfonyl)amine

A solution of 2-(napth-2-yloxy)-4-nitroaniline (300 mg, 1.07 mmol) andlutidine (0.1145 g, 1.07 mmol) in dry CH₂ Cl₂ (25 mL) was cooled to -23°C. To the solution was added trifluromethanesulfonic anhydride (0.604 g,2.14 mmol). The reaction was stirred for 0.15 h at -23° C., the coolingbath was removed, the reaction warmed to 0° C. and quenched by addingexcess water. The two-phased solution was partitioned between ethylacetate and brine. The organic layer was washed (1×, 10% aqueous HCl;1×, saturated aqueous NaHCO₃ ; 1×, brine), dried (Na₂ SO₄), filtered andconcentrated in vacuo. Purification by flash chromatography (silica gel;25% ethyl acetate/hexane) afforded the compoundN-(2-(napth-2-yloxy)-4-nitrophenyl)-N,Nbis(trifluoromethanesulfonyl)amine.

Preparation of 2-(napth-2-yloxy)-4-nitroaniline

A solution of N-(2-(napth-2-yloxy)-4-nitrophenyl!)methanesulfonamide(0.17 g, 0.474 mmol) in acetic acid(4 mL), water (1 mL), andconcentrated sulfuric acid (3 mL) was refluxed for 3 h, cooled, andneutralized by pouring into a saturated aqueous solution of sodiumcarbonate. The resulting mixture was extracted (2×, ethyl acetate). Thecombined organic extracts were washed (2×, brine), dried (Na₂ SO₄),filtered and concentrated in vacuo to afford a brown glassy film.Purification by flash chromatography (silica gel; 15% ethylacetate/hexane) afforded the compound 2-(napth-2-yloxy)-4-nitroaniline.¹ HNMR (300 MHz, CDCL₃) δ4.63(s, 2H), 6.82 (d, J=9 Hz; 1H), 7.24 (dd;J=9,3 Hz; 1H), 7.36 (d; J=2.5 Hz; 1H), 7.46 (pd; J=7.5,7.5,7.5,7.5,2.5Hz; 2H), 7.73 (d; J=7.5 Hz; 1H), 7.7 (s; 1H), 7.83 (br d; J=7.5 Hz; 1H),7.87 (d; J=9 Hz; 1H), 7.95 (dd; J=9,3 Hz; 1H), 8.04.

EXAMPLE 7N-(2-(6fluoronaphthal-2-yloxy)4-nitrophenyl)trifluoromethanesulfnamide##STR22##

The title compound was prepared following the procedure described inExample 6, but employingN-(2-6fluoronaphth-2-yloxy)4nitrophenyl)trifluoromethanesulfnamide inlieu of N-2-(naphth-2-yloxy)4-nitrophenyl)trifluoromethanesulfnamide.

We claim:
 1. A compound having the formula: ##STR23## wherein Z isselected from the group consisting of:(a) naphthyl; and (b) substitutednaphthyl wherein the hydrogen atom attached to one to four of the carbonatoms is replaced with a substituent independently selected from R₄wherein R₄ is --F, --CN, --Cl, or --CF₃ ; R₁ is selected from the groupconsisting of --NO₂, --CN, --Cl, and CF₃ ; R₂ is --H or R₁ and R₂ takentogether with the atoms to which they are attached define a 5-, 6- or7-membered saturated carbocyclic or saturated heterocyclic ring having asingle heteroatom which is oxygen, nitrogen or sulfur wherein thecarbocyclic or heterocyclic ring is unsubstituted or substituted withone or two substituents selected from the group consisting of oxo, alkyland hydroxy; and R₃ is selected from the group consisting of lower alkyland CH_(n) F.sub.(3-n) wherein n is 0, 1, 2 or 3;or a pharmaceuticallyacceptable salt or prodrug thereof.
 2. The compound according to claim 1wherein Z is as defined therein, R₁ is --NO₂, R₂ is H, and R₃ is CH₃ ora pharmaceutically acceptable salt or prodrug thereof.
 3. A compoundselected from the group consistingofN-(4-Nitro-2-(naphth-2'-yloxy)phenyl)methanesulfonamide; (A-176229.0)N-(4-Nitro-2-(6'-fluoronaphth-2'-yloxy)phenyl)methanesulfonamide;(A-154307)or a pharmaceutically acceptable salt or prodrug thereof.
 4. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound having theformula: ##STR24## wherein Z is selected from the group consistingof:(a) naphthyl; and (b) substituted naphthyl wherein the hydrogen atomattached to one to four of the carbon atoms is replaced with asubstituent independently selected from R₄ wherein R₄ is --F, --CN,--Cl, or --CF₃ ; R₁ is selected from the group consisting of --NO₂,--CN, --Cl, and CF₃ ; R₂ is --H or R₁ and R₂ taken together with theatoms to which they are attached define a 5-, 6- or 7-membered saturatedcarbocyclic or saturated heterocyclic ring having a single heteroatomwhich is oxygen, nitrogen or sulfur wherein the carbocyclic orheterocyclic ring is unsubstituted or substituted with one or twosubstituents selected from the group consisting of oxo, alkyl andhydroxy; and R₃ is selected from the group consisting of lower alkyl andCH_(n) F.sub.(3-n) wherein n is 0, 1, 2 or 3;or a pharmaceuticallyacceptable salt or prodrug thereof.
 5. The pharmaceutical composition ofclaim 4 wherein Z is as defined therein, R₁ is --NO₂, R₂ is H, and R₃ isCH₃.
 6. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a therapeutically effective amount of a compoundselected from the group consistingofN-(4-Nitro-2-(naphth-2'-yloxy)phenyl)methanesulfonamide; (A-176229.0)and N-(4-Nitro-2-(6'-fluoronaphth-2'-yloxy)phenyl)methanesulfonamide;(A-154307)or a pharmaceutically acceptable salt or prodrug thereof.
 7. Amethod for inhibiting prostaglandin synthesis comprising administeringto a mammal in need of such treatment a therapeutically effective amountof a compound having the formula: ##STR25## wherein Z is selected fromthe group consisting of:(a) naphthyl; and (b) substituted naphthylwherein the hydrogen atom attached to one to four of the carbon atoms isreplaced with a substituent independently selected from R₄ wherein R₄ is--F, --CN, --Cl, or --CF₃ ; R₁ is selected from the group consisting of--NO₂, --CN, --Cl, and CF₃ ; R₂ is --H or R₁ and R₂ taken together withthe atoms to which they are attached define a 5-, 6- or 7-memberedsaturated carbocyclic or saturated heterocyclic ring having a singleheteroatom which is oxygen, nitrogen or sulfur wherein the carbocyclicor heterocyclic ring is unsubstituted or substituted with one or twosubstituents selected from the group consisting of oxo, alkyl andhydroxy; and R₃ is selected from the group consisting of lower alkyl andCH_(n) F.sub.(3-n) wherein n is 0, 1, 2 or 3;or a pharmaceuticallyacceptable salt or prodrug thereof.
 8. The method of claim 7 wherein Zis as defined therein, R₁ is --NO₂, R₂ is H, and R₃ is CH₃.
 9. A methodfor inhibiting prostaglandin synthesis comprising administering to amammal in need of such treatment a therapeutically effective amount of acompound selected from the group consistingofN-(4-Nitro-2-(naphth-2'-yloxy)phenyl)methanesulfonamide; (A-176229.0)and N-(4-Nitro-2-(6'-fluoronaphth-2'-yloxy)phenyl)methanesulfonamide;(A-154307)or a pharmaceutically acceptable salt or prodrug thereof.